Lapachol / lipid-P Cancer Research Results

LapC, Lapachol: Click to Expand ⟱
Features:
Lapachol is a natural naphthoquinone originally derived from the heartwood of the lapacho tree (Tabebuia species).
-lapachol is an analog of shikonin

Pathways:

Oxidative Stress and ROS Generation
–Like many quinones, lapachol can undergo redox cycling that generates reactive oxygen species (ROS).
-Oxidative damage to DNA, proteins, and lipids, thereby promoting cancer cell death.
-cell cycle at specific checkpoints (commonly at G0/G1 or G2/M phases)
-Inhibition of the NF‑κB signaling pathway
–MAPK Pathways

-ic50 cancer cells 10-50uM, normal cells higher (existence of a therapeutic window)

Lapachol — a naturally occurring prenylated 1,4-naphthoquinone, chemically 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone, found principally in the heartwood of Tabebuia/Handroanthus species such as pau d’arco/lapacho. It is a natural-product small molecule and experimental pharmacologic agent rather than an approved anticancer drug. Lapachol has several experimentally supported molecular targets, notably RSK2, PKM2 and DHODH, with additional evidence for topoisomerase inhibition and quinone-associated redox effects.

Primary mechanisms (ranked):

  1. RSK2 inhibition with suppression of downstream proliferative signaling and induction of mitochondrial intrinsic apoptosis.
  2. PKM2 inhibition with suppression of aerobic glycolysis, reduced ATP generation and increased metabolic vulnerability.
  3. DHODH inhibition with suppression of de novo pyrimidine synthesis and proliferation.
  4. Mitochondrial intrinsic apoptosis involving BAX, cytochrome c and caspase-3/7 activation.
  5. Topoisomerase I and II inhibition with impaired DNA topology, DNA damage and antiproliferative effects in selected models.
  6. Quinone redox cycling and ROS generation (secondary/context-dependent), potentially enhanced in cells capable of efficient quinone reduction.
  7. Cell-cycle arrest and suppression of clonogenic growth and migration, varying substantially by tumor model.

Bioavailability / PK relevance: Lapachol is orally absorbable in animal models, with reported oral bioavailability approximately 55–77% for lapachol in one preclinical PK study; this should not be assumed to represent human exposure. It binds strongly to human serum albumin and is relatively hydrophobic, affecting distribution and free-drug exposure. Historical human studies found that plasma concentrations believed necessary for anticancer activity required very large oral doses, creating a major dose-limiting translational problem.

In-vitro vs systemic exposure relevance: Most modern anticancer studies use micromolar lapachol concentrations, frequently in the approximately 10–100 μM range depending on model and endpoint. Historical clinical work indicates that maintaining sufficiently high systemic concentrations is difficult without substantial toxicity; therefore many in-vitro anticancer exposures may exceed realistically sustainable human free-drug exposure. Derivatives and metal complexes of lapachol can be considerably more potent but should not be interpreted as evidence for parent lapachol itself.

Clinical evidence status: Preclinical with limited historical human exposure. A small early cancer clinical study was performed in the 1970s, but development was discontinued because high drug concentrations were required and dose-limiting toxicity, particularly anticoagulant effects and prolonged prothrombin time, emerged. No validated modern RCT evidence supports lapachol as an anticancer treatment, and it is not an approved cancer therapy.

Lapachol Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 RSK2 signaling ↓ ↔ / ↓ (context-dependent) R/G Suppression of proliferative signaling Direct RSK2 inhibition demonstrated in ESCC models; growth inhibition was strongly dependent on RSK2 expression and was associated with intrinsic apoptosis.
2 PKM2 and glycolysis ↓ ↔ / ↓ (context-dependent) R/G Reduced glycolytic ATP production Lapachol inhibits purified PKM2 and tumor-cell PKM2 activity, decreases glycolytic flux and ATP, and increases reliance on mitochondrial oxidative metabolism.
3 DHODH and pyrimidine synthesis ↓ ↓ proliferating cells R/G Reduced de novo pyrimidine synthesis Direct DHODH binding and inhibition are supported by biochemical studies and a human DHODH–lapachol crystal structure. The mechanism is not cancer-specific and may also suppress proliferating lymphocytes.
4 Mitochondrial intrinsic apoptosis ↑ ↔ / ↑ (dose-dependent) R/G Caspase-dependent apoptosis Associated with ↑ BAX, ↑ cytochrome c release, ↑ caspase-3/7 activity and PARP cleavage in responsive cancer models.
5 Topoisomerase I and II ↓ ↓ (high concentration) R/G DNA damage and impaired DNA topology Inhibition of TOP1 and TOP2 has been demonstrated in glioma models. Evidence is less extensive than for RSK2, PKM2 and DHODH.
6 ATP and metabolic fitness ↓ ↔ / ↓ (dose-dependent) R/G Energetic stress Primarily downstream of PKM2 inhibition and metabolic rewiring rather than a discrete molecular target.
7 Mitochondrial respiration ↑ (context-dependent) ↔ R Compensatory oxidative metabolism PKM2 inhibition can shift melanoma cells away from glycolysis toward increased oxygen consumption, creating vulnerability to mitochondrial perturbation.
8 ROS and quinone redox cycling ↑ (context-dependent) ↑ (dose-dependent) P/R Oxidative stress and macromolecular damage Mechanistically plausible for reducible naphthoquinones and supported by naphthoquinone redox biology, but ROS should be treated as a secondary mechanism for parent lapachol rather than its best-established primary anticancer target.
9 DNA damage ↑ ↑ (high concentration) R/G Genotoxic stress Can arise downstream of topoisomerase inhibition and oxidative stress.
10 Cell-cycle progression ↓ ↓ (dose-dependent) G Cell-cycle arrest Sub-G1 accumulation and other checkpoint effects have been reported; the specific checkpoint varies by cell type and experimental system.
11 Clonogenic survival ↓ Not established G Reduced long-term proliferative capacity Demonstrated in ESCC and more recent bladder cancer models.
12 Migration ↓ Not established G Reduced tumor-cell motility Reported in bladder cancer and other experimental models; molecular basis remains less well established than the core metabolic targets.
13 Vitamin K recycling ↓ ↓ R/G Anticoagulant effect Lapachol inhibits vitamin K epoxide reductase and vitamin K quinone reductase. This provides a mechanistic explanation for prolonged prothrombin time observed at high exposure and represents an important safety limitation.
14 Clinical Translation Constraint ↓ therapeutic feasibility ↑ toxicity risk G Exposure-limited clinical utility Anticancer activity generally requires substantial micromolar exposure. Historical clinical studies encountered difficulty achieving effective plasma levels without anticoagulant toxicity; no modern clinical anticancer efficacy has been established.
P: 0–30 min    R: 30 min–3 hr    G: >3 hr

lipid-P, lipid peroxidation: Click to Expand ⟱
Source:
Type:
Lipid peroxidation is a chain reaction process in which free radicals (often reactive oxygen species, or ROS) attack lipids containing carbon-carbon double bonds, especially polyunsaturated fatty acids. This attack results in the formation of lipid radicals, peroxides, and subsequent breakdown products.
Lipid peroxidation can cause damage to cell membranes, leading to increased permeability and disruption of cellular functions. This damage can initiate a cascade of events that may contribute to carcinogenesis.
The byproducts of lipid peroxidation, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), can form adducts with DNA, leading to mutations. These mutations can disrupt normal cellular processes and contribute to the development of cancer.
Lipid peroxidation damages cell membranes, disrupts cellular functions, and can trigger inflammatory responses. It is a marker of oxidative stress and is implicated in many chronic diseases.

Negative Prognostic Indicator: In many cancers, high levels of lipid phosphates, particularly S1P, are associated with poor prognosis, indicating a more aggressive tumor phenotype and potential resistance to therapy.
Mixed Evidence: The prognostic significance of lipid phosphates can vary by cancer type, with some studies showing that their expression may not always correlate with adverse outcomes.
Scientific Papers found: Click to Expand⟱
8167- LapC,    Characterization of lapachol cytotoxicity: contribution of glutathione depletion for oxidative stress in Saccharomyces cerevisiae
- in-vitro, Nor, NA
*GSH↓, *SOD1↓, *lipid-P↑, *ROS↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Total Targets: 0

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

GSH↓, 1,   lipid-P↑, 1,   ROS↑, 1,   SOD1↓, 1,  
Total Targets: 4

Scientific Paper Hit Count for: lipid-P, lipid peroxidation
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:300  Target#:453  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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